Abstract Lymphangioleiomyomatosis (LAM) is a devastating pulmonary disease almost exclusively affecting young women. LAM is characterized by smooth muscle cell infiltration and emphysema-like lung destruction. LAM is associated with mutations in the TSC2 resulting in activation of the mammalian target of rapamycin complex 1 (mTORC1). Although the mTORC1 inhibitor rapamycin stabilizes lung function and improves symptoms in LAM patients, lung function declines after drug discontinuation and the long-term safety and efficacy of the drug are unknown. There is therefore an urgent, unmet need for more effective therapies. Despite many advances in understanding the role of mTOR-dependent pathways in LAM progression, the reason that LAM primarily affects women are not understood. In the MILES trial, lung function declined 5 times more rapidly in premenopausal patients than post menopausal patients, suggesting that estrogen plays a major role in lung function decline. Our central hypothesis is that estrogen promotes prostaglandin biosynthesis and action programs in TSC2-deficient cells, leading to tumor growth and emphysema-like destruction and pulmonary function decline. In Aim 1, we will test the hypothesis that estrogen and TSC2 loss act synergistically to regulate transcription machinery that controls COX-2 expression and prostaglandin biosynthesis. We further postulate that prostaglandin metabolites enhanced by estrogen and TSC2-deficiency modulate the function of LAM patient-derived cells and airway structural cells. In Aim 2, we will test the hypothesis that estrogen and TSC2 deficiency synergistically enhance prostaglandin production, thereby promoting destructive lung remodeling and pulmonary function decline. We postulate that that the combined suppression of prostaglandin biosynthesis by a COX1/2 inhibitor and mTORC1 blockade with sirolimus will induce regression of estrogen- promoted established lung lesion and improve pulmonary physiology in mouse models of LAM. In Aim 3, we will test the hypothesis that the combined suppression of prostaglandin biosynthesis by a COX1/2 inhibitor and mTORC1 blockade with sirolimus will be well-tolerated and more effective than sirolimus alone. We further propose that blood-based prostaglandin metabolites are biomarkers for disease severity and therapeutic responses in LAM. Throughout the proposal, we will utilize innovative, state-of-the-art technology including ChIP-Seq to identify estrogen-regulated transcription factor activation, non-invasive imaging of in vivo models for evidence of lung tumor and COX-2 activities, and application of real-time three-dimensional computer- tomography coupled with lung physiology in mouse models. The significance of this project is that it will reveal for the first time how estrogen contributes to the destructive lung remodeling and pulmonary functional decline. This study will have high impact because LAM leads progresses much more rapidly in women with an intact estrogen axis and results in respiratory failure and death. Despite many advances in understanding mTOR- dependent pathways, there remains a critical need for more effective therapeutic options for women with LAM.